We identify and topographically localize inflammatory, degenerative, and malignant cells, as well as their products and related molecules, in patient specimens and animal tissues. We analyze these cells and their products mainly by routine pathology, immunohistochemistry, and molecular pathology. The application of cutting-edge technology, such as microdissection combined with molecular techniques (PCR, RT-PCR, genotyping, etc.) allows us to provide a more accurate pathological diagnosis (assessment) and understand the pathogenesis of the disease. These technologies and findings will guide us in selecting the most targeted treatments for patients. We also study the mechanisms of different ocular diseases from various animal models. Using animal models, we can assess the efficacy of novel therapeutic agents for various ocular diseases. In FY2014, we accomplished the following in our research: 1. Molecular Pathology of Age-Related Macular Degeneration (AMD): AMD is the leading cause of irreversible severe central vision loss among the elderly in the world. It is projected that AMD will affect 3 million Americans over the age of 50 by the year 2020. The pathology of AMD is characterized by the accumulation of soft drusen, retinal pigment epithelium (RPE) and photoreceptor degeneration, geographic atrophy, and/or exudation with choroidal neovascularization in the macula. While several risk factors, including age, race, smoking, diet, oxidative stress and inflammation have been linked to AMD, the etiology and pathogenesis of the disease remain largely unclear. Current knowledge has shown that AMD development is strongly influenced by genetic factors. Treatment options for neovascular AMD include intravitreal injections of anti-vascular endothelial growth factor (VEGF); however, treatment options for geographic atrophy AMD are extremely limited. In FY2014, we reported several single nucleotide polymorphisms in the TIM3/SYN3, RAD51B, and FBN2 genes associated with AMD. We documented aberrant expression of interleukin-17A (IL17A) and the receptor IL17RC in the macula of AMD patients. In vitro, IL17A induces RPE cell death characterized by the accumulation of cytoplasmic lipids and autophagosomes with subsequent activation of pro-apoptotic Caspase-3 and Caspase-9. This pathology is reduced by siRNA knockdown of IL17RC. We investigate the link among macrophage, inflammasome, and IL-17 in AMD. We also found therapeutic effectiveness of adeno-associated virus vector encoding soluble IL-17 receptor, pimento epithelium-derived factor (PEDF), and platelet-derived growth factor-C (PDGF-C) on our double deficient Ccl2 and Cx3cr1 on Crb1rd8 background mice, an AMD model. Although the findings in the mouse model may not necessarily translate to findings in humans, they could still provide useful information for our understanding AMD pathogenesis and investigating potential therapeutic targets. 2. Ocular Lymphoma: Primary vitreoretinal lymphoma (PVRL), previously called primary intraocular lymphoma (PIOL), is a rare and fatal ocular malignancy. The diagnosis of PVRL is often challenging as it can masquerade as chronic uveitis. We published an article describing a method to differentiate PVRL from uveitis by using the level of miRNA-155 in the vitreous, which was significantly lower in PVRL. In human tissues, miRNA-155 regulates numerous transcriptional factors such as FOXP3, NFKB1, TGFB1, and AKT1. The interaction of microRNA-155 and those transcriptional factors plays an important role in innate immune responses and tumorigenesis. However, vitreal miRNA level does not offer an advantage to the ratio of IL-10 and IL-6 levels for the diagnosis of PVRL. We reviewed 853 patients at the NIH Uveitis clinic between 2004-2012 and found 21 (2.5%) with neoplastic masquerade syndrome. They were more likely to be older, non-African Americans who presented with unilateral, posterior uveitis. We also reported the difficulty in diagnosing PVRL, which often requires a high degree of clinical suspicion by physician and more than one invasive procedure (63% of the 27 PVRL patients at NIH) to make the diagnosis. We also reported an association between autofluorescent granularity patterns (hyperautofluorescent spots) with active PVRL. 3. New Pathology and Pathogenesis of Ocular Diseases: In collaboration with Drs. H. Nida Sen of NEI, Deborah Goldstein of Northwestern University, and Janet Davis of Bascom Palmer Institute, we edited a Special Issue on Gender and Uveitis. This special issue includes 10 articles and attempts to identify gender- and sex-based differences in infectious and noninfectious autoimmune uveitis, for example, multiple sclerosis in women, juvenile idiopathic arthritis in girls, and syphilitic uveitis in HIV-infected male patients. Clinical manifestations and courses may appear differently between genders in certain uveitides. We raised the relevance of HIF expression in von Hippel-Lindau (VHL) associated retinal hemangioblastoma. We provided unique and new molecular pathology in the eyes with sympathetic uveitis, ocular sarcoidosis, and viral retinitis.